Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:118])[C:82]2[CH:81]=[C:80]([C:83]3[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:103])[C@@H:94]([NH:98][C:99](=[O:102])[O:100][CH3:101])[CH:95]([CH3:97])[CH3:96])[CH:89]([CH3:91])[CH3:90])[NH:86][CH:87]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:104]1[CH:105]=[CH:106][C:107]3[N:111]=[C:110]([C@@H:112]4[CH2:116][CH2:115][CH2:114][NH:113]4)[NH:109][C:108]=3[CH:117]=1)=[CH:74][CH:75]=2>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:113]1[CH2:114][CH2:115][CH2:116][C@H:112]1[C:110]1[NH:109][C:108]2[CH:117]=[C:104]([C:73]3[CH:74]=[CH:75][C:76]4[C:77]5[C:82](=[CH:81][C:80]([C:83]6[N:84]=[C:85]([C@@H:88]([NH:92][C:93](=[O:103])[C@@H:94]([NH:98][C:99]([O:100][CH3:101])=[O:102])[CH:95]([CH3:97])[CH3:96])[CH:89]([CH3:90])[CH3:91])[NH:86][CH:87]=6)=[CH:79][CH:78]=5)[C:70]([F:69])([F:118])[C:71]=4[CH:72]=3)[CH:105]=[CH:106][C:107]=2[N:111]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N[C@H](c1nc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]c5c4)ccc2-3)c[nH]1)C(C)C)C(C)C

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-1-((S)-1-(4-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)-9H-fluoren-2-yl)-1H-imidazol-2-yl)-2-methylpropylamino)-3-methyl-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 873.92 [M+H]+. (62 mg, 37%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br-].[K+]>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: BrCc1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96.1 %

Procedure:
A slurry of 41.7 g (0.3 mol) of o-nitrophenol in 200 ml of ethanol was added to a stirred, cooled solution of 19.8 g (0.3 mol) of 85% potassium hydroxide in 300 ml of ethanol; a voluminous yellow-orange precipitate of the potassium salt separated. After stirring at room temperature for 45 minutes, a solution of 35.7 ml (0.3 mol) of benzyl bromide in 100 ml of ethanol was added portionwise (no temperature rise) and the mixture was stirred at room temperature for 30 minutes, then gradually heated to reflux. The solid went into solution as the color lightened from red to light yellow and potassium bromide separated. After refluxing for 3 hours, the mixture was cooled and most of the ethanol removed on a rotary evaporator. The residue was shaken with 300 ml of ether and 100 ml of water and the layers separated. The aqueous phase was extracted with ether (2×100 ml) and the combined ether layers were washed with 50 ml of water and 50 ml of saturated sodium chloride solution. After drying over magnesium sulfate, the solvent was evaporated to give 66.1 g of a red-orange oil which was fractionated to yield 44.3 g of the title A compound as a yellow oily product, b.p. 163°-166° (0.2 mm). Lit. b.p. 127°-129° (0.05 mm); J. Org. Chem., 37, 1848 (1972).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].[N:13]#[C:14]Br>O.C(#N)C>[NH2:13][C:14]1[NH:1][C:2]2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][C:11]=2[N:12]=1
Reactant: N#CBr
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O
Solvent: CC#N
Product: COC(=O)c1ccc2nc(N)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
300 mg (1.8 mmol) of methyl 3,4-diaminobenzoate was stirred in 5 ml of water. 0.5 ml of a solution of 5 M of cyanogen bromide in acetonitrile was added to the obtained mixture, and they were stirred at room temperature for 20 minutes. The mixture was filtered. Aqueous ammonia was added to the filtrate. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the title compound was obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12]([OH:14])=[O:13])[C:4]([CH3:15])=[CH:3]1.[C:16](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C=O)C>[OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:7][CH2:8][CH2:9][CH2:10]2)[C@@H:5]([C:12]([O:14][CH3:16])=[O:13])[C:4]([CH3:15])=[CH:3]1
Reactant: O=C([O-])[O-]
Reactant: CC1=C[C@H](O)CC2(CCCC2)[C@H]1C(=O)O
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Reaction time: 0.5 h
Yield: 36 %

Procedure:
At 5° C., a solution of the crude trans-9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylic acid obtained (22.7 g) in DMF (150 ml) was treated with potassium carbonate (16.3 g, 118 mmol) and stirred for 30 min. The resulting mixture was then treated within 6 min. with methyl iodide (13.4 ml, 215 mmol), stirred for 2 h at 20° C., poured into cold 2N aqueous HCl (200 ml), and extracted twice with hexane (150 ml). The combined organic phases were washed with water (100 ml), with a saturated aqueous solution of NaCl (150 ml), dried (MgSO4), and concentrated, giving crude trans-methyl 9-hydroxy-7-methylspiro[4.5]dec-7-ene-6-carboxylate (12.85 g, 36%).
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=O)[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>O1CCOCC1.CCOC(C)=O>[S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]3)=[S:46])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=S)[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)cnc32)cc1
Temperature: 60 °C
Yield: 127.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamoyl)-piperidine-1-carboxylate (7.58 g, 13.8 mmol) in 1,4-dioxane (130 mL) was added Lawesson's reagent (3.37 g, 8.32 mmol) and the reaction mixture was heated to about 60° C. for about 2 h then cooled to ambient temperature and concd under reduced pressure. The crude residue was dissolved in EtOAc (40 mL) and washed with saturated aqueous NaHCO3, (3×40 mL), brine (30 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The crude material was purified by silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to afford (R)-tert-butyl 3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamothioyl)piperidine-1-carboxylate (5.6 g, 74%, UV purity 97%): LC/MS (Table 1, Method b) Rt=2.60 min; MS m/z: 530 (M+H)+.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:32][CH2:33][C@H:34]([NH:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:43])=[O:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CCOC(C)=O>[CH2:38]([O:37][C:35](=[O:36])[C@@H:34]([NH:40][S:41]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)(=[O:42])=[O:43])[CH2:33][NH:32][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH3:39]
Reactant: CCOC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
N—Cbz-glycine (339 mg, 1.62 mmol) was dissolved in 8 mL EtOAc, cooled to −15° C., then NMM (196 μL, 1.8 mmol) and isobutyl chloroformate (230 μL, 1.8 mmol) were added. After 20 min, the mixed anhydride solution was added to amine 3-4 (0.50 mg, 1.6 mmol) suspended in 5 mL EtOAc and the reaction was warmed to RT for 90 min. Following dilution with EtOAc, the mixture was washed with water, sat. NaHCO3, 5% KHSO4, and brine, dried (MgSO4), filtered and concentrated. Flash chromatography (silica, 75% EtOAc/hexane) provided amide 3-5 as a colorless oil.
Reaction SMILES: C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.[Br:17]Br.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[O:27])=[CH:22][CH:21]=1>C(OCC)C>[Br:17][CH:28]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:26](=[O:27])[C:23]1[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=1
Reactant: BrBr
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)C(Br)c1ccc(Cl)cc1

Procedure:
The benzoin starting material can be prepared by adding bromine (18.1g) dropwise to a stirred solution of 4,4'-dichlorodeoxybenzoin (30g) in dry diethylether (400ml). The solution is stirred for a further hour and evaporated to provide crude α-bromo-4,4'-dichlorodeoxybenzoin (40g) which when recrystallised from methanol has a melting point of 81°-83°.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:4]#[N:5].[NH3:14].OS(O)(=O)=O.[OH-:20].[Na+]>CO>[NH2:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:3]=1[C:4]([NH2:5])=[O:20]
Reactant: N
Reactant: N#Cc1c(F)cccc1C(F)(F)F
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1c(N)cccc1C(F)(F)F
Temperature: 100 °C

Procedure:
100 mg (0.5 mmol) 2-fluoro-6-trifluoromethyl-benzonitrile are combined with 1 ml of a 7 M ammonia solution in methanol and heated in the microwave for 20 min. at 100° C. Then the solvent is eliminated in vacuo, the crude product is combined with 1 ml of conc. H2SO4 and heated for 2.5 h at 80° C. Then the reaction mixture is stirred into ice water, neutralised with 1 M NaOH and extracted twice with 150 ml dichloromethane and three times with 160 ml of ethyl acetate. The organic phase is dried with MgSO4 and the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier material used is silica gel and the eluant is dichloromethane, to which 4% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution have been added.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9]OC)=[CH:6][N:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.Cl.[CH2:17]1[CH2:21]OC[CH2:18]1>[Cl-].[Na+].O>[CH:18]1([CH2:9][O:8][C:7]2[C:2]([F:1])=[CH:3][C:4]([C:12]([O:14][CH3:15])=[O:13])=[N:5][CH:6]=2)[CH2:17][CH2:21]1
Reactant: C1CCOC1
Reactant: COCOc1cnc(C(=O)OC)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(F)c(OCC2CC2)cn1
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 4-fluoro-5-(methoxymethoxy)pyridine-2-carboxylate (1.80 g) in THF (20 mL) was added 6 N hydrochloric acid (5 mL), and the mixture was stirred at 70° C. for 20 min. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in DMF (20 mL), potassium carbonate (2.31 g) and (bromomethyl)cyclopropane (1.22 mL) were added thereto, and the mixture was stirred with heating at 70° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.07 g).
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[CH3:18][Si:17]([CH3:20])([CH3:19])[N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)N1CCCCCC1=O

Procedure:
Caprolactam, commercially available from Maybridge, (10.0 g, 88.0 mmol), Et3N (14.8 mL, 106 mmol) and chlorotrimethylsilane (13.5 mL, 106 mmol) were dissolved in toluene (60 mL) and refluxed under Ar for 3 h. The reaction was filtered and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]2[O:31][CH:30]([CH2:32]Br)[CH2:29][C:28]=2[CH:34]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2([OH:13])[CH2:8][CH2:9][N:10]([CH2:32][CH:30]3[CH2:29][C:28]4[CH:34]=[C:24]([O:23][CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH:25]=[CH:26][C:27]=4[O:31]3)[CH2:11][CH2:12]2)=[CH:14][CH:15]=1
Reactant: BrCC1Cc2cc(OCc3ccccc3)ccc2O1
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Product: OC1(Cc2ccc(F)cc2)CCN(CC2Cc3cc(OCc4ccccc4)ccc3O2)CC1

Procedure:
The title compound MS: m/e=448.6 (M+H+) was prepared from 4-(4-fluoro-benzyl)-piperidin-4-ol and 5-benzyloxy-2-(RS)-bromomethyl-2,3-dihydro-benzofuran.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[C:12]([N:16]=[C:17]=[S:18])([CH3:15])([CH3:14])[CH3:13]>C(O)C>[C:12]([NH:16][C:17]([NH:1][C@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4])=[S:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1ccccc1
Yield: 98.8 %

Procedure:
The process is performed as in Example 2, starting with 5 g of (R)-(+)2-amino-3-phenyl-1-propanol in 50 cm3 of ethanol and 5.7 g of tert-butyl isothiocyanate at a temperature in the region of 20° C. for 16 hours. After an identical work-up, 8.7 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(phenylmethyl)ethyl]thiourea are obtained in the form of a white solid melting at 107° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[C:3]([SH:12])=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1S
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1S

Procedure:
A solution of 3,4-dichloro-2-mercaptobenzoic acid (17.78 g) and concentrated sulphuric acid (3.75 ml) in ethanol was heated at reflux for 20 hours. After cooling the mixture was evaporated and the residue suspended in dichloromethane, washed with water, sodium bicarbonate, water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with hexane to give ethyl 3,4-dichloro-2-mercaptobenzoate (7.96 g) as a yellow solid NMR (CDCl3) 1.3(t,3H), 4.25(q,2H), 6.75(s, 1H), 7.15(d, 1H), 7.8(d, 1H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23](O)=[O:24])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:32][CH:33](C)[CH2:34][OH:35].CN1[CH:42]=[CH:41]N=C1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([C:23]([N:32]4[CH2:42][CH2:41][O:35][CH2:34][CH2:33]4)=[O:24])[CH:26]=[CH:27][CH:28]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Reactant: CC(N)CO
Reactant: Cn1ccnc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)N4CCOCC4)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.3 %

Procedure:
A mixture of 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.121 mmol), 2-aminopropan-1-ol (12 mg, 0.133 mmol), 1-methyl-1H-imidazole (40 mg, 0.484 mmol) and EDCI (92 mg, 0.484 mmol) in dichloromethane (10 mL) was stirred at room temperature for 20 h then concentrated. The residue was purified by Prep-TLC (silica gel, 200-300 mesh, methanol:dichloromethane=1:30) to afford (3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenyl)(morpholino)methanone (30 mg, 51%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.84 (s, 1H), 8.11-8.01 (m, 3H), 7.61-7.54 (m, 3H), 7.44 (t, 1H, J=8.1 Hz), 6.30 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.4 Hz), 4.27-4.21 (m, 1H), 3.79-3.44 (m, 10H), 2.18-2.04 (m, 3H), 1.79 (brs, 1H), 1.19 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 484, tR=1.738 min, HPLC: 99.76% at 214 nm, 99.56% at 254 nm, tR=5.698 min.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([N:30]=[C:31]=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([CH2:35][NH2:36])[OH:34]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([NH:30][C:31]([NH:36][CH2:35][CH2:33][OH:34])=[O:32])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCO
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(NC(=O)NCCO)C3)ccc2n1CC1CCC(F)(F)CC1
Yield: 43.9 %

Procedure:
Following the same procedure in Example 105, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(3-isocyanatoazetidin-1-yl)sulfonyl]-1H-benzimidazole (0.095 mmol) and ethanolamine (12 uL, 12 mg, 0.19 mmol) in THF (6.0 mL). The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 22 mg (44%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.49-1.65 (m, 2 H), 1.68 (s, 9 H), 1.70-1.86 (m, 4 H), 2.02-2.14 (m, 2 H), 2.19-2.36 (m, 1 H), 3.13 (t, J=5.57 Hz, 2 H), 3.48 (t, J=5.57 Hz, 2 H), 3.64 (dd, J=8.50, 6.35 Hz, 2 H), 3.99 (t, J=8.11 Hz, 2 H), 4.17-4.27 (m, 1 H), 4.55 (d, J=7.42 Hz, 2 H), 7.93 (dd, J=8.79, 1.76 Hz, 1 H), 8.06 (d, J=8.79 Hz, 1 H), 8.17 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=528.3; Anal. Calcd for C24H35F2N5O4S+0.90 TFA+1.0H2O+0.10 EtOAc (658.29): C, 47.99; H, 5.93; N, 10.64. Found: C, 47.99; H, 5.95; N, 10.68.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]([NH2:15])=O)=[CH:9][C:8]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[Br:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH:12]=[N:11][C:10]([C:13]#[N:15])=[CH:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: NC(=O)c1cc2c(cn1)[nH]c1ncc(Br)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc2c(cn1)[nH]c1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
To a cooled solution (0° C.) of a mixture of 3-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid amide (5.0 g, 17.2 mmol) and triethylamine (24.0 mL, 172 mmol) in THF (200 mL) was slowly added trifluoroacetic anhydride (12.0 mL, 86 mmol). Upon complete addition, the reaction mixture was allowed to warm to ambient temperature and the stirring was continued for an additional 4 h. After this time, the solvent was removed in vacuo and the resultant residue was loaded onto H-MN. The residue was then purified by flash chromatography (silica, 330 g column, ISCO, 0-100% ethyl acetate in hexane) to afford the title compound as a pale brown solid (2.30 g, 49%). 1H NMR (DMSO-D6, 300 MHz): 13.05 (s, 1H), 9.08-9.04 (m, 2H), 8.91 (d, J=1.1 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H). LCMS (Method B): RT=2.98 min, M+H+=271, 273.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([C:19]2[NH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:16]=[C:15]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:14]=1)[C:5]([O:7]C)=[O:6].O.O.[OH-].[Li+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([C:19]2[NH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[CH:16]=[C:15]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][CH3:33])[CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Methyl 3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzoate (611 mg, 1.42 mmol) synthesized in Example 43 was dissolved in methanol (18 mL), and water (3 mL) and lithium hydroxide monohydrate (298 mg, 7.10 mmol) were added, followed by stirring at 60° C. for 4 hours under nitrogen atmosphere. To the reaction solution, water (50 mL) was added, and extraction was carried out twice with ethyl acetate (40 mL), followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-75%) to afford the desired compound (519 mg, yield 88%) as a white solid.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29](=O)[C:28]5[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=5[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:42][NH2:43]>CO>[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]5=[N:42][NH:43][C:31](=[O:33])[C:27]6[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=65)[NH:22][CH:21]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C4CC4)CC3)c1)C(c1ccccc1)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: O=C(c1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1)N1CCN(C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
A mixture of methyl 3-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (64 mg, 0.12 mmol) in 85% hydrazine monohydrate (5 mL) and methanol (2 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give 9-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (8 mg, yield 13%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.73-0.81 (m, 4H), 1.18-1.19 (m, 1H), 3.20-3.71 (m, 8H), 4.23-4.25 (d, J=10.0 Hz, 1H), 4.59-4.61 (d, J=8.4 Hz, 1H), 7.08-7.26 (m, 10H), 7.45-7.54 (m, 2H); LC-MS (ESI) m/z: 520 (M+1)+.